Several diseases have been characterized based on the presence of abnormal protein aggregates found within cells, including Parkinson's disease and Lou Gehrig's disease. Ubiquitin is found conjugated to proteins found within these inclusions. Being a signal for proteasome- mediated degradation, the presence of ubiquitin in these aggregates suggests that either the recognition or the degradation machinery is perturbed in these cells, causing an accumulation of undegraded protein. Another type of protein degradation is that which is mediated by the lysosome, an acidic organelle harboring most of the proteolytic enzymes of the cell. Several pathways exist for proteins to be delivered to the lysosome, including the autophagic pathway. Recently, researchers have begun to identify the first molecular players involved in formation of autophagic vesicles, double-membrane bound vesicles which are transported to lysosomes for ultimate degradation. My goal is to begin to characterize the role of these proteins in degradation of protein and protein complexes during the autophagic pathway. In the first specific aim, I propose that these proteins are involved in an early stage of autophagosome formation, perhaps by recognizing such ill-fated proteins. In the second and third aims, I propose to examine the role of a subset of these proteins in signaling the formation of the autophagic vesicles. This work is designed to begin to understand the basis of the inclusion-forming diseases by examining the critical balance between protein synthesis and protein turnover within cells.